9-112268162-C-T

Variant names:

• chr9-112268162-C-T
• rs556943992
• NM_001163788.4:c.238G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001163788.4(PTBP3):​c.238G>A​(p.Val80Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,611,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V80A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: PTBP3 NM_001163788.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.828

Genes affected

PTBP3 (HGNC:10253): (polypyrimidine tract binding protein 3) The protein encoded by this gene binds RNA and is a regulator of cell differentiation. The encoded protein preferentially binds to poly(G) and poly(U) sequences in vitro. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.049712867).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTBP3	NM_001163788.4	c.238G>A	p.Val80Ile	missense_variant	Exon 4 of 14	ENST00000374257.6	NP_001157260.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTBP3	ENST00000374257.6	c.238G>A	p.Val80Ile	missense_variant	Exon 4 of 14	2	NM_001163788.4	ENSP00000363375.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.0000404 AC: 10 AN: 247734 AF XY: 0.0000224

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000895

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000548

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000274 AC: 40 AN: 1458812 Hom.: 0 Cov.: 30 AF XY: 0.0000179 AC XY: 13 AN XY: 725606

Gnomad4 AFR exome AF: 0.0000601 AC: 2 AN: 33278

Gnomad4 AMR exome AF: 0.000160 AC: 7 AN: 43810

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26012

Gnomad4 EAS exome AF: 0.0000504 AC: 2 AN: 39652

Gnomad4 SAS exome AF: 0.0000234 AC: 2 AN: 85394

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53384

Gnomad4 NFE exome AF: 0.0000225 AC: 25 AN: 1111256

Gnomad4 Remaining exome AF: 0.0000332 AC: 2 AN: 60274

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152242 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74452

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.0000654 AC: 0.000065445 AN: 0.000065445

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.000193 AC: 0.000192901 AN: 0.000192901

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000294 AC: 0.0000294048 AN: 0.0000294048

Gnomad4 OTH AF: 0.000474 AC: 0.000473934 AN: 0.000473934

Alfa AF: 0.0000952 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 01, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.331G>A (p.V111I) alteration is located in exon 1 (coding exon 1) of the PTBP3 gene. This alteration results from a G to A substitution at nucleotide position 331, causing the valine (V) at amino acid position 111 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.030	.;.;.;T;.;T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.71	T;T;T;T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.050	T;T;T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	-0.91	.;.;.;N;.;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.62	N;N;N;N;N;N
REVEL	Benign	0.15
Sift	Benign	0.33	T;T;T;T;T;T
Sift4G	Benign	0.24	T;T;T;T;T;.
Polyphen		0.020	B;B;.;B;.;.
Vest4		0.17
MutPred		0.30		.;.;.;Loss of catalytic residue at V108 (P = 0.0469);.;.;
MVP		0.39
MPC		0.10
ClinPred		0.075	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.18
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs556943992; hg19: chr9-115030442; COSMIC: COSV52957718; COSMIC: COSV52957718;